BACKGROUND

Penetrating brain injury (PBI) is a leading cause of combat mortality but local outcome data is limited. The authors examined combat-related PBI cases to describe patient characteristics and identify clinical and radiologic predictors of functional recovery

This is a retrospective cohort study of military personnel aged 18–56 years with combat-related PBI referred to VLGH AFPMC between January 2017 to June 2022. The authors collected demographics data, injury mechanism, pre-hospital and transfer details, admission clinical and radiologic findings, treatments, and follow-up outcomes. The Glasgow Outcome Scale (GOS), dichotomized into unfavorable (GOS 1–3) and favorable (GOS 4–5), was used to assess functional status. Associations were tested with Fisher’s Exact Test.

Thirty-seven patients met inclusion criteria: 31 survivors with follow-up and 6 who died in hospital. All were male; gunshot wounds accounted for 81% of injuries. At a median follow-up of 27 months, among survivors, 74% had a Glasgow Coma Scale (GCS) of 15 and 45% achieved good recovery (GOS 5). Pre-hospital timing measures (evacuation time, interval to surgery, and transfer delays) were not significantly associated with outcome. Favorable outcomes correlated strongly with higher admission GCS (p < 0.001), preserved baseline motor function (p < 0.001), smaller hemorrhage volume (p = 0.01), and injury limited to a single lobe (p < 0.001). Unfavorable outcomes were associated with intracranial infection, post-traumatic seizures, and need for multiple surgeries (all p < 0.001).

Functional recovery after combat-related PBI in this cohort was principally determined by initial neurologic status, injury extent, and subsequent complications The lack of association with pre-hospital timing possibly reflects survivorship bias and incomplete capture of early fatalities.

Neurological diseases are a major health concern, and brain injury is a typical pathological process in various neurological disorders. Different biomarkers in the blood or the cerebrospinal fluid are associated with specific physiological and pathological processes. They are vital in identifying, diagnosing, and treating brain injuries. In this review, we described biomarkers for neuronal cell body injury (neuron-specific enolase, ubiquitin C-terminal hydrolase-L1, αII-spectrin), axonal injury (neurofilament proteins, tau), astrocyte injury (S100β, glial fibrillary acidic protein), demyelination (myelin basic protein), autoantibodies, and other emerging biomarkers (extracellular vesicles, microRNAs). We aimed to summarize the applications of these biomarkers and their related interests and limits in the diagnosis and prognosis for neurological diseases, including traumatic brain injury, status epilepticus, stroke, Alzheimer's disease, and infection. In addition, a reasonable outlook for brain injury biomarkers as ideal detection tools for neurological diseases is presented.
Humans ; Biomarkers/cerebrospinal fluid* ; Nervous System Diseases/diagnosis* ; Brain Injuries/metabolism* ; Phosphopyruvate Hydratase/cerebrospinal fluid* ; Glial Fibrillary Acidic Protein/blood* ; S100 Calcium Binding Protein beta Subunit/blood* ; tau Proteins/cerebrospinal fluid* ; Ubiquitin Thiolesterase/blood* ; Myelin Basic Protein/cerebrospinal fluid* ; Neurofilament Proteins/blood* ; MicroRNAs/blood* ; Brain Injuries, Traumatic/metabolism*

Human ; Craniocerebral Trauma ; Coronary Artery Disease ; Heart Block ; Heart Failure

Hypoxic-ischemic (HI) brain damage poses a high risk of death or lifelong disability, yet effective treatments remain elusive. Here, we demonstrated that miR-100-5p levels in the lesioned cortex increased after HI insult in neonatal mice. Knockdown of miR-100-5p expression in the brain attenuated brain injury and promoted functional recovery, through inhibiting the cleaved-caspase-3 level, microglia activation, and the release of proinflammation cytokines following HI injury. Engineered extracellular vesicles (EVs) containing neuron-targeting rabies virus glycoprotein (RVG) and miR-100-5p antagonists (RVG-EVs-Antagomir) selectively targeted brain lesions and reduced miR-100-5p levels after intranasal delivery. Both pre- and post-HI administration showed therapeutic benefits. Mechanistically, we identified protein phosphatase 3 catalytic subunit alpha (Ppp3ca) as a novel candidate target gene of miR-100-5p, inhibiting c-Fos expression and neuronal apoptosis following HI insult. In conclusion, our non-invasive method using engineered EVs to deliver miR-100-5p antagomirs to the brain significantly improves functional recovery after HI injury by targeting Ppp3ca to suppress neuronal apoptosis.
Animals ; MicroRNAs/metabolism* ; Extracellular Vesicles/metabolism* ; Mice ; Recovery of Function/physiology* ; Hypoxia-Ischemia, Brain/therapy* ; Mice, Inbred C57BL ; Antagomirs/administration & dosage* ; Male ; Animals, Newborn ; Apoptosis/drug effects* ; Brain Injuries/metabolism* ; Glycoproteins ; Peptide Fragments ; Viral Proteins

The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a crucial role in the prognosis of subarachnoid hemorrhage (SAH). WNK1 kinase negatively regulates NLRP3 in various inflammatory conditions, but its role in early brain injury (EBI) after SAH remains unclear. In this study, we used an in vivo SAH model in rats/mice and AAV-WNK1 intraventricular injection to investigate its neuroprotective mechanisms. WNK1 expression was significantly reduced in SAH patient blood and SAH model brain tissue, correlating negatively with microglial activation. AAV-WNK1 alleviated brain edema, neuronal necrosis, behavioral deficits, and inflammation by inhibiting NLRP3 inflammasome activation. In hemin-stimulated BV-2 cells, WNK1 overexpression reduced NLRP3 activation and inflammatory cytokines. Chloride counteracted WNK1's inhibitory effects, and WNK1 suppressed P2X7R-induced NLRP3 activation. Mechanistically, WNK1 functioned via the OXSR1/STK39 pathway. These findings highlight WNK1 as a key regulator of intracellular chloride balance and neuroinflammation, presenting a potential therapeutic target for SAH treatment.
Animals ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Subarachnoid Hemorrhage/complications* ; Inflammasomes/metabolism* ; Rats ; Mice ; Neuroinflammatory Diseases/metabolism* ; WNK Lysine-Deficient Protein Kinase 1/genetics* ; Male ; Humans ; Chlorides/metabolism* ; Mice, Inbred C57BL ; Rats, Sprague-Dawley ; Brain Injuries/metabolism* ; Microglia/metabolism* ; Protein Serine-Threonine Kinases

Mild repetitive head injury is a serious health problem with long-term negative consequences. Changes in brain neurobiology were assessed with MRI in a model of head injury designed to reflect the human experience. Rats were maintained on a reverse light-dark cycle and head impacted daily at 24 h intervals over three days while fully awake under red light illumination. There was no neuroradiological evidence of brain damage. Rats were imaged for changes in blood brain barrier permeability, edema and gray matter microarchitecture, and resting state functional connectivity. Data were registered to a 3D MRI rat atlas with 173 segmented brain areas providing site-specific information on each imaging modality. Changes in BBB permeability were minimal and localized to the hippocampus and cerebellum. There was evidence of cytotoxic edema in the basal ganglia, thalamus, and cerebellum. There was a global decrease in connectivity and an increase in gliosis in the thalamus, cerebellum, and hippocampus. This study shows a sequelae of neuropathology caused by mild repetitive head injury that is commonly observed in clinical practice using MRI in patients. As such, it may serve as a model for testing the efficacy of new therapeutics using any or all of the measures as biomarkers to assess drug efficacy.
Animals ; Magnetic Resonance Imaging/methods* ; Disease Models, Animal ; Brain/physiopathology* ; Male ; Rats ; Rats, Sprague-Dawley ; Blood-Brain Barrier/diagnostic imaging* ; Multimodal Imaging ; Wakefulness/physiology* ; Craniocerebral Trauma/physiopathology*

Post-cardiac arrest brain injury (PCABI) remains the main cause of death and poor prognosis in patients after resuscitation. In June 2024, the International Liaison Committee on Resuscitation (ILCOR) released a scientific statement on improving the prognosis of PCABI based on relevant research progress. The statement proposed the pathological mechanism of PCABI, explored the reasons why previous preclinical data could not be translated into clinical practice, and outlined possible future directions for advancement. This article interprets the key content of the 2024 ILCOR scientific statement on improving the prognosis of PCABI, hoping to provide reference and assistance for domestic medical staff to understand and apply this scientific statement.
Humans ; Heart Arrest/therapy* ; Brain Injuries/therapy* ; Cardiopulmonary Resuscitation ; Prognosis ; Resuscitation

OBJECTIVE: To investigate the mechanism of human embryonic stem cell-derived mesenchymal stem cells (hESC-MSC) in alleviating brain injury after resuscitation in swine with cardiac arrest (CA). METHODS: Twenty-nine healthy male large white swine were randomly divided into Sham group (n = 9), cardiopulmonary resuscitation (CPR) group (n = 10) and hESC-MSC group (n = 10). The Sham group only completed animal preparation. In CPR group and hESC-MSC group, the swine model of CA-CPR was established by inducing ventricular fibrillation for 10 minutes with electrical stimulation and CPR for 6 minutes. At 5 minutes after successful resuscitation, hESC-MSC 2.5×10⁶/kg was injected via intravenous micropump within 1 hour in hESC-MSC group. Venous blood samples were collected before resuscitation and at 4, 8, 24, 48 and 72 hours of resuscitation. The levels of neuron specific enolase (NSE) and S100B protein (S100B) were detected by enzyme linked immunosorbent assay (ELISA). At 24, 48 and 72 hours of resuscitation, neurological deficit score (NDS) and cerebral performance category (CPC) were used to evaluate the neurological function of the animals. Three animals from each group were randomly selected and euthanized at 24, 48, and 72 hours of resuscitation, and the hippocampus tissues were quickly obtained. Immunofluorescence staining was used to detect the distribution of hESC-MSC in hippocampus. Immunohistochemical staining was used to detect the activation of astrocytes and microglia and the survival of neurons in the hippocampus. The degree of apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL). RESULTS: The serum NSE and S100B levels of brain injury markers in CPR group and hESC-MSC group were significantly higher than those in Sham group at 24 hours of resuscitation, and then gradually increased. The levels of NSE and S100B in serum at each time of resuscitation in hESC-MSC group were significantly lower than those in CPR group [NSE (μg/L): 20.69±3.62 vs. 28.95±3.48 at 4 hours, 27.04±5.56 vs. 48.59±9.22 at 72 hours; S100B (μg/L): 2.29±0.39 vs. 3.60±0.73 at 4 hours, 2.38±0.15 vs. 3.92±0.50 at 72 hours, all P < 0.05]. In terms of neurological function, compared with the Sham group, the NDS score and CPC score in the CPR group and hESC-MSC group increased significantly at 24 hours of resuscitation, and then gradually decreased. The NDS and CPC scores of hESC-MSC group were significantly lower than those of CPR group at 24 hours of resuscitation (NDS: 111.67±20.21 vs. 170.00±21.79, CPC: 2.33±0.29 vs. 3.00±0.00, both P < 0.05). The expression of hESC-MSC positive markers CD73, CD90 and CD105 in the hippocampus of hESC-MSC group at 24, 48 and 72 hours of resuscitation was observed under fluorescence microscope, indicating that hESC-MSC could homing to the damaged hippocampus. In addition, compared with Sham group, the proportion of astrocytes, microglia and apoptotic index in hippocampus of CPR group were significantly increased, and the proportion of neurons was significantly decreased at 24, 48 and 72 hours of resuscitation. Compared with CPR group, the proportion of astrocytes, microglia and apoptotic index in hippocampus of hESC-MSC group decreased and the proportion of neurons increased significantly at 24 hours of resuscitation [proportion of astrocytes: (14.33±1.00)% vs. (30.78±2.69)%, proportion of microglia: (12.00±0.88)% vs. (27.89±5.68)%, apoptotic index: (12.89±3.86)% vs. (52.33±7.77)%, proportion of neurons: (39.44±3.72)% vs. (28.33±1.53)%, all P < 0.05]. CONCLUSIONS Application of hESC-MSC at the early stage of resuscitation can reduce the brain injury and neurological dysfunction after resuscitation in swine with CA. The mechanism may be related to the inhibition of immune cell activation, reduction of cell apoptosis and promotion of neuronal survival.
Animals ; Heart Arrest/therapy* ; Cardiopulmonary Resuscitation ; Swine ; Humans ; Male ; Human Embryonic Stem Cells/cytology* ; Mesenchymal Stem Cell Transplantation ; Mesenchymal Stem Cells/cytology* ; Phosphopyruvate Hydratase/blood* ; Brain Injuries/therapy* ; S100 Calcium Binding Protein beta Subunit ; Apoptosis ; Disease Models, Animal

OBJECTIVE: To identify early potential risk factors for hospital-acquired pneumonia (HAP) in patients with mild traumatic brain injury (mTBI), construct a risk prediction model, and evaluate its predictive efficacy. METHODS: A case-control study was conducted using clinical data from mTBI patients admitted to the neurosurgery department of Changzhou Second People's Hospital from September 2021 to September 2023. The patients were divided into two groups based on whether they developed HAP. Clinical data within 48 hours of admission were statistically analyzed to identify factors influencing HAP occurrence through univariate analysis. Least absolute shrinkage and selection operator (LASSO) regression analysis was employed for feature selection to identify the most influential variables. The dataset was divided into training and validation sets in a 7:3 ratio. A multivariate Logistic regression analysis was then performed using the training set to construct the prediction model, exploring the risk factors for HAP in mTBI patients and conducting internal validation in the validation set. Receiver operator characteristic curve (ROC curve), decision curve analysis (DCA), and calibration curve were utilized to assess the sensitivity, specificity, decision value, and predictive accuracy of the prediction model. RESULTS: A total of 677 mTBI patients were included, with 257 in the HAP group and 420 in the non-HAP group. The significant differences were found between the two groups in terms of age, maximum body temperature (MaxT), maximum heart rate (MaxHR), maximum systolic blood pressure (MaxSBP), minimum systolic blood pressure (MinSBP), maximum respiratory rate (MaxRR), cause of injury, and laboratory indicators [C-reactive protein (CRP), procalcitonin (PCT), neutrophil count (NEUT), erythrocyte sedimentation rate (ESR), fibrinogen (FBG), fibrinogen equivalent units (FEU), prothrombin time (PT), activated partial thromboplastin time (APTT), total cholesterol (TC), lactate dehydrogenase (LDH), prealbumin (PAB), albumin (Alb), blood urea nitrogen (BUN), serum creatinine (SCr), hematocrit (HCT), hemoglobin (Hb), platelet count (PLT), glucose (Glu), K⁺, Na⁺], suggesting they could be potential risk factors for HAP in mTBI patients. After LASSO regression analysis, the key risk factors were enrolled in the multivariate Logistic regression analysis. The results revealed that the cause of injury being a traffic accident [odds ratio (OR) = 2.199, 95% confidence interval (95%CI) was 1.124-4.398, P = 0.023], NEUT (OR = 1.330, 95%CI was 1.214-1.469, P < 0.001), ESR (OR = 1.053, 95%CI was 1.019-1.090, P = 0.003), FBG (OR = 0.272, 95%CI was 0.158-0.445, P < 0.001), PT (OR = 0.253, 95%CI was 0.144-0.422, P < 0.001), APTT (OR = 0.689, 95%CI was 0.578-0.811, P < 0.001), Alb (OR = 0.734, 95%CI was 0.654-0.815, P < 0.001), BUN (OR = 0.720, 95%CI was 0.547-0.934, P = 0.016), and Na⁺ (OR = 0.756, 95%CI was 0.670-0.843, P < 0.001) could serve as main risk factors for constructing the prediction model. Calibration curves demonstrated good calibration of the prediction model in both training and validation sets with no evident over fitting. ROC curve analysis showed that the area under the ROC curve (AUC) of the prediction model in the training set was 0.943 (95%CI was 0.921-0.965, P < 0.001), with a sensitivity of 83.6% and a specificity of 91.5%. In the validation set, the AUC was 0.917 (95%CI was 0.878-0.957, P < 0.001), with a sensitivity of 90.1% and a specificity of 85.0%. DCA indicated that the prediction model had a high net benefit, suggesting practical clinical applicability. CONCLUSIONS The cause of injury being a traffic accident, NEUT, ESR, FBG, PT, APTT, Alb, BUN, and Na⁺ are identified as major risk factors influencing the occurrence of HAP in mTBI patients. The prediction model constructed using these parameters effectively assesses the likelihood of HAP in mTBI patients.
Humans ; Risk Factors ; Case-Control Studies ; Logistic Models ; Healthcare-Associated Pneumonia/epidemiology* ; Brain Injuries, Traumatic/complications* ; Male ; Female ; ROC Curve ; Pneumonia/etiology* ; Middle Aged ; Adult

OBJECTIVE: To observe the protective effect of Fisetin on sepsis-associated brain injury and explore its possible mechanism from the perspective of ferroptosis. METHODS: Sprague-Dawley (SD) rats (6-8-week-old male) were randomly divided into three groups: sham operation group (Sham group), colonic ligation and puncture (CLP) induced sepsis model group (CLP group) and Fisetin preprocessing group (CLP+Fisetin group), with 18 rats in each group (12 for observing survival rate and 6 for indicator testing). The CLP+Fisetin group was given Fisetin solution 50 mg×kg^-1×d^-1 by gavage continuously for 5 days before CLP, with dimethyl sulfoxide (DMSO) as the solute, while Sham group and CLP group were given the same dose of DMSO. The model was established at 2 hours after the last gavage. The general condition of each group of rats were observed, and the 10-day mortality were record. The behavioral testing (new object recognition experiment, elevated cross maze experiment) were performed after 7 days of modeling. After 24 hours of modeling, nerve reflex scoring was performed, and then the rats were euthanized and brain tissue was collected. The pathological changes of brain tissue were observed under a microscope by hematoxylin-eosin (HE) staining, the deposition of iron ion in brain tissue was observed by Prussian blue staining. The content of iron in brain tissue was determined by tissue iron kit, and the content of malondialdehyde (MDA) in brain tissue was determined by colorimetry. The expressions of tumor necrosis factor-α (TNF-α), neuron damage marker S100β, nuclear factor E2-related factor 2 (Nrf2), heme oxygenases-1 (HO-1) and glutathione peroxidase 4 (GPX4) were detected by Western blotting. RESULTS: On day 10 post-operation, 12, 3, and 7 animals survived in the Sham group, CLP group, and CLP+Fisetin group, respectively. Compared with the Sham group, rats in the CLP group showed significantly decreased nerve reflex score, new object discrimination index and open arm dwell time. HE staining showed arranged disorderly of neuronal cells, cytoplasm deep staining, nuclear condensation, unclear structures, neuron loss, and significant inflammation in the hippocampus in the hippocampus. Prussian blue staining showed iron ion deposition in the brain tissue. The contents of iron and MDA in brain tissue were elevated, and the expressions of TNF-α and S100β were up-regulated, while the expressions of Nrf2, HO-1, and GPX4 were down-regulated. Compared with the CLP group, the CLP+Fisetin group showed significantly increased neurological reflex score (7.33±1.15 vs. 4.67±1.53), improved new object discrimination index (0.44±0.02 vs. 0.32±0.04), and longer open arm dwell time (minutes: 78.33±9.29 vs. 41.15±9.64). Neuronal cells in the hippocampus were more organized, with less cytoplasmic staining, nuclear condensation, reduced neuronal loss, and fewer inflammatory cells. Iron ion deposition was reduced, and the contents of iron ions and MDA in brain tissue were decreased [iron ion (μg/g): 151.27±14.90 vs. 224.69±17.64, MDA (μmol/g): 470.0±44.3 vs. 709.3±65.4]. The expressions of TNF-α and S100β were significantly decreased (TNF-α/GAPDH: 0.651±0.060 vs. 0.896±0.022, S100β/GAPDH: 0.685±0.032 vs. 0.902±0.014), while the expressions of Nrf2, HO-1, and GPX4 were significantly increased (Nrf2/GAPDH: 0.708±0.108 vs. 0.316±0.112, HO-1/GAPDH: 0.694±0.022 vs. 0.538±0.024, GPX4/GAPDH: 0.620±0.170 vs. 0.317±0.039). All differences were statistically significant (all P < 0.05). CONCLUSION Fisetin pretreatment can inhibit ferroptosis and reduce sepsis-associated brain injury by Nrf2/HO-1/GPX4 pathway.
Animals ; Ferroptosis/drug effects* ; Rats, Sprague-Dawley ; NF-E2-Related Factor 2/metabolism* ; Sepsis/complications* ; Male ; Rats ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Neurons/drug effects* ; Signal Transduction ; Brain Injuries/metabolism* ; Flavonols ; Flavonoids/pharmacology* ; Heme Oxygenase-1/metabolism* ; Heme Oxygenase (Decyclizing)